Introduction
The purpose of this review is to collate and summarize some of the available scientific data regarding potential causes, aggravations and therapies in the fibromyalgia/chronic fatigue (FMS/CFS) and like syndromes. This review is not intended to be encyclopedic in scope but rather to give some data-driven rationale for common therapies clinically recognized as useful in these syndromes. Additionally, the data presented are limited to injection therapies. As injection therapies are a broad topic and the technical points of safe administration are numerous and beyond the scope of this article, limited discussion of technique-oriented data (such as dose and administration) will be given. It is assumed that if practitioners wish to use this information to treat patients, they have the prerequisite training in the safe administration of any substances mentioned by injection therapies.

Additionally, it should be noted that noninjection therapies typically crucial to the treatment of FMS/CFS, while not discussed in this review, are assumed to be known and practiced concurrently. These include but are not limited to endocrine support, immune and infectious therapies, sleep hygiene and therapies, digestive support and diet therapy, as well as many others. And finally any injectable nutrient mentioned below should be added to the oral repletion therapy of the FMS/CFS patient both between and after the injection therapy if the individual patient gastrointestinal function allows.

Basis of the Disorders
Much has been published regarding the potential causes of FMS/CFS. Most clinicians agree that these conditions are multifactorial and patient specific. Potential partial causes or aggravations of FMS/CFS include hippocampal dysfunction, neurotransmitter imbalance and autoimmune attack, lifestyle and physical activity deficits, oxidative stress and mitochondrial dysfunction, methyl cycle defects, seasonal affective disorder, anemia, and many others.1–15,36,52

Given the broad base of data regarding potential cause and the logical conclusion that FMS/CFS are therefore multifactorial, anecdotal positive clinical experience in broad-based therapies, both oral and injection, match the available data and make logical clinical sense. The discussion below attempts to give scientific and clinical rationale to common injection therapies that address the above causal relationships in FMS/CFS. When the term clinical experience is used in this review, it refers to the author's two decades' experience in treating FMS/CFS with multiple therapies including over 50,000 IV and injection administrations.

As a small number of reviews or studies on injection therapies in FMS/CFS exist, this review will focus on updated information regarding potential biological indications for injection therapies commonly employed in the integrative medical setting.18–20

Therapeutic Targets for Injection Therapies
Therapeutic targets for injection therapies are well suited to access some of the common potential causes of FMS/CFS. These include neurotransmitter imbalance and autoimmunity, oxidative stress and mitochondrial dysfunction, methyl cycle and other genomic defects, anemia, dehydration and like comorbidities.

Hydration
Dehydration is known to aggravate many of the CNS manifestations of FMS/CFS such as "brain fog" and to decrease quality of life in ill people.16,17 Although many nutrient formulas are hypertonic and thus not hydrating, our clinical experience shows that the desired IV formula can be made hydrating if the osmolarity is adjusted to isotonic or mildly hypotonic (170–310 mOsm/L) and that this adjustment can improve tolerance and outcome of the IV therapy. While oral hydration is always a primary goal of therapy, the addition of a hydrating type IV formula can additionally be beneficial in this population.

Vitamin C/Ascorbic Acid (ASC)
The use of ASC in IV therapy is well known and reasonably well studied and reported on elsewhere in the literature and clinical experience. Limiting the discussion to symptoms related to FMS/CFS, such as fatigue, pain, and immune deficits, ASC infusion can be a helpful addition. Use of ASC IV has been shown to improve pain in viral infections and fatigue, as well as oxidative/redox balance.7,21,22 Doses in studies were moderate (5 to 15 grams) and are amenable to admixture in other water-soluble nutrient infusions. In clinical practice, the author has seen similar results with these relatively low-dose strategies, as well as higher-dose oxidative ASC infusions in treating infectious comorbidities of FMS/CFS.

Magnesium
Long a staple of oral and injection therapies in FMS/CFS, magnesium enjoys great clinical popularity in most clinicians' assessment. Some of the things that injected magnesium can add to the therapy of FMS/CFS include NMDA/glutamate receptor activity decrease, causing lower nociception and CNS arousal, and acetylcholine blockade, causing skeletal muscle relaxation, cardiac muscle calcium channel downregulation, as well as increased cell ATP and glutathione activity.23–27 An additional benefit of injected magnesium is a relatively long therapeutic window following injection. In a human study of IV magnesium, Silver reported that tissue levels rose for 24 hours following infusion and distributed for another 24 hours, giving a total postinfusion therapeutic window of at least 48 hours following one infusion.27 The author's clinical experience has been that IM doses of 0.5 to 2 grams magnesium sulfate 50% are tolerated as well as IV doses of between 2 and 8 grams of magnesium. IV doses of this magnitude need to be appropriately diluted and started at lower doses and escalated to the patient's cardiac tolerance.

The Amino Structures Taurine and Carnitine
While many amino acids are necessary in the therapy of FMS/CFS, in the author's clinical experience, two amino structures found to be exceptionally helpful are taurine and carnitine.

Carnitine (either in the L form or the more bioavailable acetyl-L form) is useful in varied targets affecting the FMS/CFS patient, including decreasing neurotoxicity, decreasing lactic acid buildup, as well as its more commonly known biochemical function of transporting fatty acids into the mitochondria for beta oxidation-based energy production.28,29 The L-carnitine form in our clinic is administered IV at doses of 500 to 4000 mg and the acetyl-L-carnitine form at doses of 100 mg to 1000 mg in most cases.

Taurine is the master osmolyte in the human body and as such regulates distribution of the excitable ions (Na, K, Ca, Mg and Cl) to their appropriate sides of the cell membrane.30,31 In this role, the author's clinical observation has been that the addition of taurine to IV formulas containing magnesium and other excitable-tissue acting minerals causes a greater benefit as reported by patients. For example, the addition of taurine to a formula with magnesium will be perceived by patients to have a more muscle-relaxing effect in many cases. Taurine is used constantly at the cell membrane and thus depleted both in low dietary intake as well as by oxidative stressors.31 Taurine in our clinic is dosed between 200 and 1000 mg in most IV formulas.

Methyl Cycle and Genomic SNP Support
In a scientific presentation by the author, a trial was reported investigating the incidence of MTHFR defects in the general population versus a sample of race-matched patients with known FMS/CFS (n = 88).6 The incidence summarized in Table 1 was much higher for homozygous C-677 defects as well as compound heterozygous defects in the FMS/CFS sample than the general population.

Table 1

Incidence Data

Hetero
A1298C

Hetero
C677T

Compound
Hetero

Homo
A1298C

Homo
C677T

Study n = 88

23

12

19

9

22

% CFS/FMS Participants

26

13

23

10

25

% Normal population

43

43

15

11

11

% Incidence Difference

-40

-70

+53

-1

+44

Once this association was established, an active comparator interventional trial was conducted to assess what if any support of the damaged methyl pathways via nutrients would add to clinical outcomes. Addition of a balanced methyl support oral formula as well as methylated forms of injectable B12 and folate resulted in data summarized in Table 2.

Table 2

Result of treatment –
Active comparator

Hetero
A1298C

Hetero
C677T

Compound
Hetero

Homo
A1298C

Homo
C677T

Intervention % (of n)

22

25

47

50

27

% outcome improvement

+55%

+75%

+56%

+56%

+71%

The intervention in the 88 patients already receiving treatment in an integrative medical clinic for their FMS/CFS already included all the comorbidity therapies mentioned in the introduction above. Prior therapy time frame was from 1 to 5 years, and all patients were not progressing with respect to additional positive treatment or symptom outcome prior to the methyl support.

Well-rounded support for methylation (MET) as well as cystathionine beta synthase (CBS) pathways appeared well tolerated in this study. This fact creates the need for more than simple injection of a methyl donor such as 5-MTHF or methyl B12 in these patients. A therapeutic injection strategy is listed below.

Care should be taken to titrate the doses of supportive parenterals up to patient tolerance. Some younger patients will tolerate a faster titration to full dose and some not. Most patients with higher-grade defects (homozygous, compound heterozygous or heterozygous with CFS, FMS, chronic neuroinflammatory disease, and any with elevated homocysteine) who are over 35 to 40 years of age will require a slower titration but ultimately higher dosing based on our observations. Additionally, in some patients with numerous additional SNP defects, a lower and more inclusive formula may be required in order to support the other SNP defects. In our clinical experience, this is most common in patients with COMT/MAO and other like SNP defects.

Data regarding injection/parenteral support of methylation defect treatment in this setting cover a span of two decades, but due to the lack of available active-form nutrients for parenteral administration, some interpretation is necessary. Older recommendations were generally safe but lacked the agents available currently such as parenteral 5-MTHF and methyl B12.32–34 Newer interventional trials used injection-grade 5-MTHF and hydroxyl-B12 with success and patient tolerance.35

Injectable Treatment Strategies
(Note: Oral supportive agents are recommended to augment these parenteral agents if tolerated by the patient.)

Methyl donor support including methyl B12 2.5–5 mg IM once to twice weekly (methyl B12 can be compounded from 2.5 to 5 mg/mL).

Direct 5-MTHF pathway support: 5-MTHF ramp up 1–10 mg IM once to twice weekly (5-MTHF can be compounded as 2.5 to 5 mg/mL). In patients in whom 5-MTHF and/or methyl B12 are too stimulating (as in COMT/MAO SNP defects), substitution with folinic acid (calcium folinate) and hydroxo-B12 can be made.

Notes:
· This may be painful due to the pyridoxine and B100. Recommend injecting into the deep hip muscles or lateral thigh if patient is administering at home. Additionally, 0.5 mL plain procaine or lidocaine may be added.
· May precipitate. Recommend adding the 5-MTHF to the syringe first, then the other additives. If that does not stop precipitation, the 5-MTHF may need to be in a separate syringe.
· This may be given as a slow IV push diluted with 10 mL sterile water (or normal saline). Ideally in a push syringe, add sterile water, then the 5-MTHF, then the other additives. In a higher-volume IV formula, the above doses are generally higher.

Iron Status and Ferritin
Ortancil et al. include a statement that significantly correlates with the author's clinical experience "Our study implicates a possible association between FM and decreased ferritin level, even for ferritin in normal ranges. We suggest that iron as a cofactor in serotonin and dopamine production may have a role in the etiology of FMS."36 Most commonly, oral repletion of iron stores via diet and supplement interventions is preferred. In the author's experience, in those with the other mentioned comorbidities and low ferritin of over 5 years' duration, injectable iron may be required. Clinical experience and the study by Ortancil indicate that a ferritin level over 40 (and ideally 50–75) is required to replenish the mitochondrial iron reserves as well as hematologic requirements. Both primary targets of iron stores (mitochondrial and hematologic) contribute significantly when iron stores are low.

Injectable iron is known to have a higher incidence of anaphylaxis and other high-grade adverse events than most other nutrients. As such, the clinician should have very specific and proper training before attempting injectable iron formulas, as well as available emergency medications and interventions should an adverse event occur.

In the author's clinical experience spanning over 3000 iron injections, the use of iron dextran is limited to Z-Track IM injection (due to the high rates of anaphylaxis when dextran is infused), and the gluconate and sucrose forms of iron are reserved for IV infusion. Used appropriately, all forms can raise ferritin and iron status faster than any oral repletion ever can, and clinically are associated with faster positive outcomes in low-ferritin patients. Page 1, 2